Phenotype Switching and the Melanoma Microenvironment; Impact on Immunotherapy and Drug Resistance

Abstract

Melanoma, a highly heterogeneous tumor, is comprised of a functionally diverse spectrum of cell phenotypes and subpopulations, including stromal cells in the tumor microenvironment (TME). Melanoma has been shown to dynamically shift between different transcriptional states or phenotypes. This is referred to as phenotype switching in melanoma, and it involves switching between quiescent and proliferative cell cycle states, and dramatic shifts in invasiveness, as well as changes in signaling pathways in the melanoma cells, and immune cell composition in the TME. Melanoma cell plasticity is associated with altered gene expression in immune cells and cancer-associated fibroblasts, as well as changes in extracellular matrix, which drive the metastatic cascade and therapeutic resistance. Therefore, resistance to therapy in melanoma is not only dependent on genetic evolution, but it has also been suggested to be driven by gene expression changes and adaptive phenotypic cell plasticity. This review discusses recent findings in melanoma phenotype switching, immunotherapy resistance, and the balancing of the homeostatic TME between the different melanoma cell subpopulations. We also discuss future perspectives of the biology of neural crest-like state(s) in melanoma.

Keywords: MITF; epithelial–mesenchymal transition; heterogeneity; immunotherapy; melanoma; phenotypic plasticity; resistance.

Figure 1

Depiction of phenotype switching during melanoma progression and the development of immunotherapy and drug resistance, based on the expression of MITF and MITF-related genes in the same tumor bed. Melanoma cells expressing low levels of MITF correspond to a slow-cycling and pro-invasive state (similar to “mesenchymal-like”), whereas higher levels of expression of MITF correlate with a proliferative and melanocytic state. Undifferentiated melanomas/neural-crest like (on the right side) melanomas lack activated immune cells, while melanocytic melanomas (left side) are composed of immunologically relatively more active immune cells/hot tumor microenvironment, which is also associated with melanocytic melanomas being relatively more responsive to immunotherapy or targeted drugs.

Figure 2

CTC clusters in the bloodstream are heterogeneous, and comprise cells with an MITF^high proliferative phenotype, an MITF^low invasive phenotype, pericytes, immune cells, platelets, and CAFs. The crosstalk between proliferative and invasive melanoma cell types in the CTC cluster facilitates seeding of CTCs and increased metastasis. Melanoma cells within the bloodstream are subject to severe stresses, such as loss of cell anchorage (anoikis), fluid shear stress, oxidative stress, and immune attack. The MITF^low cells participate with MITF^high cells to avoid anoikis, and the aggregation of CTCs in the bloodstream promotes avoidance of sheer forces in blood. Hypoxic conditions in the CTC clusters promotes invasion and endows circulating melanoma cells with a reactive oxygen species (ROS)-resistant phenotype that enhances CTC survival.